|
| Status |
Public on Aug 24, 2020 |
| Title |
WT/AtohKO Ileum w/ antibiotics |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
|
| Summary |
An inverse correlation between countries endemic for helminth infestation and Crohn's disease (CD) incidences has been reinforced by anecdotal but successful cases of helminth therapy for CD. Recent studies have revealed that tuft cells in the small intestine are critical for sensing helminths and directing a type 2 immune response to counteract colonization. Here, we establish an inverse relationship between chemosensory tuft cells and local tissue inflammation in CD patients as well as an established mouse model of TNF-á-induced Crohn's-like ileitis (TNFÄARE). Using a combination of mouse and organoid models, single-cell RNA-sequencing, multiplex immunofluorescence, computational analysis, metabolite mass spectrometry, and microbiome sequencing and manipulation, we identified Atonal Homolog 1 (ATOH1)-independent tuft cells, as opposed to ATOH1-dependent tuft cells, to be responsive to the commensal microbiome through the tricarboxylic acid (TCA) cycle metabolite succinate. To evaluate the ability of the malleable, ATOH1-independent tuft cell population to suppress intestinal inflammation, we administered succinate to TNFÄARE animals post onset of ileal inflammatory disease. We observed significantly reduced pathology that is exquisitely dependent on succinate-induced tuft cell specification in the disease model, leading to an anti-helminth response previously shown to suppress inflammation. Inflammation suppression was triggered by cytokines critical to anti-helminthic response, such as IL-22, IL-25, and IL-13. We provide evidence implicating the modulatory role of intestinal tuft cells in chronic intestinal inflammation, which could enable the development of CD therapies around leveraging this rare and elusive cell type.
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| Overall design |
Ileum Biological Replicates Collected from WT/AtohKO Mice treated with antibiotics; 2 WT vs 2 AtohKO (both with antibiotics)
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| Contributor(s) |
Lau K, Banerjee A, Simmons AJ |
| Citation(s) |
32828819 |
| NIH grant(s) |
| Grant ID |
Grant title |
Affiliation |
Name |
| R01 DK103831 |
Spatio-temporal dissection of epithelial cell hierarchies in gut inflammation |
Vanderbilt University Medical Center |
Ken Siu Kwong Lau |
|
| |
| Submission date |
Feb 24, 2020 |
| Last update date |
Aug 29, 2020 |
| Contact name |
Ken Lau |
| E-mail(s) |
ken.s.lau@vanderbilt.edu
|
| Phone |
6159366859
|
| Organization name |
Vanderbilt University
|
| Department |
Cell and Developmental Biology
|
| Street address |
2215 Garland Ave. MRBIV10475
|
| City |
Nashville |
| State/province |
TN |
| ZIP/Postal code |
37232 |
| Country |
USA |
| |
|
| Platforms (1) |
| GPL19057 |
Illumina NextSeq 500 (Mus musculus) |
|
| Samples (4)
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| This SubSeries is part of SuperSeries: |
| GSE145830 |
Ileal single-cell analysis in the context of inflammation focused on tuft cells |
|
| Relations |
| BioProject |
PRJNA608462 |
| SRA |
SRP250539 |
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